Classical antineoplastic therapeutic strategies such as surgery, radiation, and chemotherapy not only fail to cure the great majority of neoplasms, but their employment often leads to severe and debilitating side effects. The potential of antibodies as “magic bullets” for cancer therapy has been appreciated for nearly a century. During the past 25 years, various scientific developments have made possible the production of unlimited quantities of clinical-grade murine, chimeric, and humanized monoclonal antibodies (MoAbs).
Immunotherapy as a fourth anti-cancer therapy has already been proven to be quite effective. Intact, unconjugated MoAbs may: [1] produce anticancer effects through the immune system on the basis of interactions between the Fc portion of antibody and complement proteins and/or effector cells; [2] induce regulatory effects by neutralizing circulating ligands or blocking cell membrane receptors, thereby interfering with ligand/receptor interactions and signal transduction; [3] serve as immunogens for anti-cancer vaccines through the anti-idiotype-network cascade. Conjugated MoAbs can serve as carriers of other agents such as radioisotopes, natural toxins, chemotherapy drugs, cytokines, and immune cells. Important aspects of the antigenic target are the degree to which it is tumor-specific or tumor-associated, whether it internalizes or not, whether it is shed, the density of expression, and the physiologic significance of the antigen to the target cell.
In the 1980s investigators established the safety of antibody administration, defined certain predictable antibody-mediated toxicities, and confirmed that antibodies could reach tumor targets and produce antitumor effects. However, clinical use of nonhuman antibodies in humans is limited due to the development of an anti-globulin immune response in the host. This limitation has been overcome with the production of antibodies with varying degrees of humanization. For example, engineered chimeric human-mouse MoABs have been developed by replacing the mouse Fc region with the human constant region. Moreover, the framework regions of variable domains of rodent immunoglobulins were also replaced by their human equivalents. In 1997 rituximab (Rituxan), a mouse-human chimeric anti-CD20, became the first MoAb approved by regulatory agencies for the treatment of a human malignancy.